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Final score
examination result
attendance and respond in class
experiment record = + +
sign in andrespond in class
select question sign in andexperiment record
(100%) ( 80%) (10%) (10%)
(7 sections )
1. General Principles of Pharmacology (Yu
an)
2. Peripheral Nervous Pharmacology (Cao)
3. Central Nervous Pharmacology (Liu)
4. Cardiovascular Pharmacology (Zang)
5. Splanchnic and Blood Pharmacology (M
a)
6. Endocrine Pharmacology (Zhao)
7. Chemotherapeutic Pharmacology (Lin)
PharmacologyPharmacology
PART 1 GENERAL PRINCIPLES OF
PHARMACOLOGY
Dr. Yuan Bing-Xiang Department of Pharmacolog
y, Medical School,
Xi’an Jiaotong University, Tel: 82657724,
Email: [email protected]
1. Pharmacology can be defined as the science or course studying the interaction between drugs and bodies (living systems) including human being, animals and pathogens including pathogenic microorganisms (bacteria, virus, fungus…) , parasites and tumor cells…
Ⅰ CONCEPTION
CHAPTER 1 Introduction of Pharmacology
PharmacologyGENERAL PRINCIPLES
Drugs are the chemicals beneficially altering biochemical and physiological states of body, applied to prevent, treat or diagnose diseases.
Pharmacology
DrugsAct onBodies
Peripheral Nervous Pharmacology Central Nervous Pharmacology Cardiovascular PharmacologySplanchnic Pharmacology Blood Pharmacology Endocrine Pharmacology
Systemsof bodies
Pathogens- Chemotherapeutic Pharmacology
Antibacterial drugs; Antifungal drugs; Antivirus drugs; AntiparasiticsAnticancer drugs
GENERAL PRINCIPLES
Pharmacodynamics, PD
Pharmacokinetics, PK
Impact factors
2. Three aspects of pharmacology
drug body
PharmacologyGENERAL PRINCIPLES
* therapeutic effects* adverse reaction
E
D
1) Pharmacodynamics (drug acts on body)
effects
action(mechanism of effect)
Drugs actions effects
* Specific actions: drug-receptors; drug-ion channels; drug-enzymes; * Unspecific actions: drugs influence physical and chemical condition around cells (pH, osmosis …)
Primary actingon the target
Secondary Inducing effects in the organ or system
PharmacologyGENERAL PRINCIPLES
* dose-effect curves └→PD parameters (KD, EMAX…)
drug blood Concentration-Time curves
└→PD parameters from C-T curves: t1/2, Ka, Ke, F, Vd…
2) Pharmacokinetics (body acts on drug)
Undergoing of drug in body
absorption distribution excretion biotransformation
C-T curves
C
T
PharmacologyGENERAL PRINCIPLES
transportation
GENERAL PRINCIPLES Pharmacology
3) Impact factors
drug
Drugphysico-chemical propertydosage formbatch number
Medicationdose and route
time and intervalcourse of treat
association
PK
PD
physiolo-patho-
psycho-geno-
living habit ……
body
DrugBody
CHAPTER 2
pharmacokinetics
( body Acts on drug )
PHARMACOLOGIC PRINCIPLES
(sites of action) binding free
(accumulation) free binding
drugs po sc im
(plasma)
Free drugs
binding drugs metabolites
(renal) excretion
Metabolism (liver)
absorption
distribution
distribution
distribution
pharmacokineticsUndergoing of drugs
transporttransformation
out of body
The membranes with pore
are composed of lipids and
proteins in a ratio of 70:1.
The liquid-form double-deck
of membranes is formed
from lipid molecules; The
special proteins inserted into
the double-deck are
receptors, enzymes, ion
channels, carriers……
Ⅰ.Drug permeation across membranes1. Membrane
pharmacokinetics
O < >OO < >OO < >OO < >OO < >OO < >OO < >O
O < >OO < >O
O < >OO < >OO < >OO < >OO < >OO < >OO < >O
ATP
a Lipid diffusion
b Filtration
c Facilitated transport
d Active transport
eIon
transport
lipids
pore
carrier
ion channels
carrier
permeation across membranes
passive
A drug molecule moves from a side of membrane relatively high concentration to another side of low concentration without requiring energy, until an equilibrium has been achieved on both sides of the membrane.
2. Passive transport across membranes(down hill)
high low
equilibrium
pharmacokinetics
Lipid diffusion; Filtration; Facilitated transport
permeation across membranes
…..…..…..…..…..
…..…..…..…..
…..…..…..
…..…..…
..
…..…..…
…..
…..…..
Nonionized form Ionized form
1) Lipid diffusion ( Simple
diffusion)
ion trapping
←less polar molecules polar molecules→
The most important mechanism of drug transport
pharmacokinetics
pH (pKa) ┐ pKa is pH when Ionized rate is 50%
permeation across membranes
more lipid soluble less lipid soluble easy permeation hard permeation
Drug movement across membranes is driven by a concentration gradient after solution in the lipids of membranes.
k1
k2
k1 [H+][A-] k1 [H+][B]
Ka =──=───── Ka =──= ──── k2 [HA] k2 [BH+]
[A] [B] pKa = pH - log ─── pKa = pH - log ─── [HA] [BH+]
[A-] [B] pH - pKa = log ─── pH - pKa = log ─── [HA] [BH+]
HA (weak acids) B (weak bases) k1 k1 HA H+ + A- B + H+ BH+
k2 k2
pharmacokineticsLipid diffusion
[A-] [B]─── = 10pH - pKa ─── = 10pH - pKa
[HA] [BH+]
weak acids weak bases ★ pH↑↓→[A-]↑↓→ ★ pH↑↓→[BH+]↓↑→
Degree of ionization↑↓ degree of ionization↓↑
→lipid solution↓↑ →lipid solution↑↓
→permeation↓↑ →permeation↑↓
pharmacokinetics
[A-] [B] ─── = 10pH-pKa ─── = 10pH-pKa [HA] [BH+]
Lipid diffusion
Neither weak acids or weak bases are dissolved in same acid-base solution, the lipid solution↑, permeation↑; They are dissolved in opposite solution, the lipid solution↓, permeation↓.
pharmacokineticsLipid diffusion
For example, Bicarbonate (NaHCO3)
is very effective for treatment of acute
toxication from weak acid drugs (like
barbiturates).
why ?
① Alkalization of gastric juice →ionization↑
→ permeation↓ →absorption ↓
② Alkalization of blood plasma → permeation↓→across blood-brain barrier↓
gastric juice blood
drugdrug
blood Cerebrospinal fluid
drug drug
pH ↑ > pH[A-]↑ > [A-]
pH↑> pH[A-]↑> [A-]
Gastrolavage of NaHCO3
Intravenous drop of NaHCO3
pharmacokineticsLipid diffusion
③ Alkalization of humor (extra-cellular fluid) →ionization↑ →permeation↓
④ Alkalization of urine→ionization↑ →permeation↓→ drug tubular reabsorption↓→ excretion↑
drug drug
drug [A-]↑urine pH ↑
pH < pH↑ [A-] < [A-] ↑
blood
cell
pharmacokineticsLipid diffusion
* Water-soluble drugs with low molecular weight (Inc. some polar molecules) can diffuse through the aqueous pores of membrane.
* A almost free drugs can be filtrated across large pores of capillaries from or to plasma. (like drug distribution, glomerular filtration and absorption following im or sc injection)
2) Filtration (Aqueous diffusion):
pharmacokinetics
Small molecules (<100-200 dalton) pass through aqueous pores without requiring energy driven by concentration gradient.
filtration
The movement of a drug across the membrane could be facilitated by its special carrier and concentration gradient. In the carrier-mediated transport, the drug is released to another side of the membrane, and the carrier then returns to original side and state.
3) Facilitated transport (Carrier-mediated transport)
pharmacokineticsfacilitated transport
a. saturable process;
b. special binding to the carrier
c. cannot move against a concentration
gradient without energy.
The properties of facilitated transport are as follows:
pharmacokineticsfacilitated transport
2. Active transport (up hill)
A drug molecule moves from a side of membrane relatively low to one of high concentration with requiring energy and special carrier.
pharmacokinetics
a. saturable process
b. special binding to the carrier
c. transport against concentration gradient with consuming energy.
Active transport
For example: penicillin and probenecid
After glomerular filtration, penicillin undergoes tubular secretion (an active transport), having a very short half-life (t1/2=
20~30 min); probenecid having the same active mechanism can competitively inhibit the tubular secretion of penicillin. The t1/2 & effects of penicillin are prolonged.
Glomerular filtration (passive)
penicillin tubular Secretion (active)
Blood→tubule
Excretion of penicillin
probenecid
competitively inhibit
Blood→tubule
pharmacokineticsActive transport
H2O absorption
Tubule high osmosis
The transport of drugs from administration locale to bloodstream.
Ⅱ.Absorption
pharmacokineticsAbsorption
1. The routes of absorption
1) im or sc
Absorption of drugs in solution through filtration from subcutaneous or intramuscular injection sites to blood is limited mainly by blood perfusion rate.
pharmacokinetics
im > sc (adrenalin), why?
a. blood perfusion rate (im > sc)
b. adrenalin ┌α↑→vesseel↑(subcutaniea) → perfusion↓ └β↑→vesseel↓(skeleton muscle) →perfusion ↑
Absorption
2) po (per oral)
Drugs are absorbed in gastrointestinal tract through lipid diffusion. The absorption takes place mainly in the upper small intestine.
With oral administration of drugs, extensive gastrointestinal and hepatic metabolism may occur before the drugs are absorbed into systemic circulation and reach its site of action. This process is defined as the first-pass elimination.
pharmacokinetics
gastric mucosa small intestine mucosa
Absorption
What about weak acids?
Nitroglycerin given sublingually bypasses liver and enters the superior vena cava and, in turn, perfuses the coronary circulation, therefore is immediately effective to relive patients with angina pectoris.
3) Sublingual or rectal administration
Absorption properties of the administration a. incomplete and irregular absorption;
b. without or less First-pass elimination.
pharmacokineticsAbsorption
For example
F would be the extent and rate of drug absorption following extravascular administration (like orally). F could be the absolute rate of a drug, used for indicating the absorption amount (AUC) compared with that of intravenous administration, or relative rate of a pharmaceutical product, used for indicating the absorption amount (AUC) compared with that of standard preparation in the same administration (same route and dose).
2. Bioavailability (F)
pharmacokineticsAbsorption
A (drug amounts in body)=───────────── ×100% D (administered dose)
AUC (area under extravascular curve)=────────────────── ×100% AUC (area under intravenous curve)
AUC (test pharmaceutics)=────────────── ×100% AUC (standard preparation)
test
TT
standardC
iv
po
pharmacokinetics
F (absolute)
F(absolute)
F (relative)
im
C
Absorption
The transport of drugs from
bloodstream to various organs
and tissues, or to different p
hysical compartments of bod
y.
Ⅲ.Distribution
pharmacokineticspharmacokinetics
Distribution
1. Compartments
According to perfusion rate of drugs to various organs and tissues, body can abstractly be divided into one, two or more parts (one compartment model, two compartments model, three…).
pharmacokineticsDistribution
Drugs within the model are assumed to be
distributed just to the organs or tissues with high
blood flow and rapid uniform (brain, heart, liver,
kidneys, lungs, active muscle, …). The C-T curve
have one phase: elimination. The distribution is
too rapid to be found in the C-T curve..
。。
Distribution
T
1) One compartment model
Kadrug
Ke
drug
Ke
Distribution
Co
Tt1/2 t1/2
C
1/21/4
Ke。。
KCdt
dC
KteCC 0
t303.2
KlogClogC 0
logC
T
logC0
pharmacokineticsDistribution
2) Two compartments model
Drugs are not only distributed to the organs or
tissues with rich blood perfusion (central
compartment), but also to that with low blood flow
(peripheral compartment: fat, skin, bone, resting
muscle). The C-T curve have two phases:
a. The distribution rate is known as the alpha
half-life, t1/2α.
b. The elimination rate is known as the beta
half-life, t1/2β.
Ka
Ke
K1
K2
T
β
α
C
Ct = CAe-kαt + CBe-kβt
。。
pharmacokineticsDistribution
α
β
distribution
elimination
peripheral central
Vd is that drug in a plasma concentration should
be solved in apparent volume of body fluid includi
ng the general circulation and the tissues. Vd is u
sed for measuring distribution range, relating the
amount in the body (A) to the concentration of dru
g (C ) in blood.
total amount of drug in body, A(mg) F.D Vd(L) =──────────────────── =── concentration of drug in plasma, C(mg/L) C
2. Apparent volume of distribution (Vd)
pharmacokineticsDistribution
1) Barrier: blood-brain barrier, placental barrier)
a. less ionized drug & small particle→permeable
b. inflammation→permeable
iodium thyroid
2) active transport→tissues concentration↑ active transport
3) regional blood flow
subcutaneous < intramuscular
3. Factors influencing distribution
pharmacokineticsDistribution
free drug + plasma binding drug (active form) (inactive storage form) small particle of drug large particle of drug →rapid filtration → no filtration → rapid distribution → → no distribution → ┌ action ┌no action└elimination └no elimination (metabolism & excretion)
moving balance
4) Binding rate to plasma : binding ratio to plasma protein at the therapeutic dosage.
pharmacokineticsDistribution
Characters of binding to plasma a. saturability
Dose↑→binding rate ↓→free drug ↑
Malnutritionliver function↓
Renal function↓
free drug↑
Plasma-albumin↓
binding rate↓
b. Unspecific competition
combinationcompetive
bindingbinding
rate↓ free drug↑
B 92% (8%) →90% (10%) →effect (toxicity) ↑┅ ┅ ┅ ┅ ┅
A 98% (2%) ┅ ┅ ┅ ┅ ┅→96% (4%) →effect (toxicity)↑↑→bleeding2%↓
warfarin
phenylbutazone
Phase 1
oxidation reduction hydrolysis
drug activity↓
Phase 2conjugation
toxicity↓ binding rate↓ more polar excretion↑
Inactivation
Prodrugs activation
Ⅳ.Biotransformationmainly in the liver
hepatic microsomal mixed function oxidase system
pharmacokineticsBiotransformation
with glycuronic acid
1. two phases
2. Factors affecting drug metabolism
1) drugs
enzyme inducer
Chlorpromazine phenobarbital
activity of enzyme↑
→tolerance (dosage↑)
enzyme inhibiter
phenylbutazone chloromycetin
activity of enzyme↓
→hypersensitivity (dosage↓)
pharmacokineticsBiotransformation
For example:
* Deficiency in the activity of acetylase results peripheral neuritis from isoniazid;
* Absence of glucose 6-phosphate dehydrogenase (G6PD) results hemolytic anemia from:
2) Pharmacogeneticshereditary variation in handling of drugs
pharmacokineticsBiotransformation
sulfonamides vitamin K (antihemorrhagic)primaquine (antimalarial agent) phenacetin (antipyretic analgesic) broad beans.
Glucose
G-6-P
ATP
ADP
6-PG Acid
G6PD↓NADP
NADPH↓
GSSG
GSH↓
H2O2 ↑↑
H2O↓
Hemolytic anemia
Oxidizing agent
Absence of G6PD
sulfonamides vitamin K primaquine anminopyrine broad beans
+
Biotransformation pharmacokinetics
3) Physiological and pathological condition
Age
elder
newborn
deficiency of drug elimination
toxicity of drugs
newborn
gray syndrome chloromycetin
numerous drugselder
toxicity↑
Less dosage
pharmacokineticsBiotransformation
liver functionrenal function
For example:
完善 flaw
Circulatory failure
Illness
hepatic disease
enzymeproduction↓
hypersensitivity
Plasma production↓
drug metabolism↓
Plasma binding↓→free drug↑
Renal dysfunction
Plasma loss↑
Should dosage↓
pharmacokineticsBiotransformation
Drugs and their metabolites in circu
lation are excreted by kidneys, bile, mi
lk, sweat and lungs.
Ⅴ.Excretion of drugs
pharmacokinetics
glomerular filtration
tubular water reabsorption
Plasma (Drug & metabolites)
hyperosmotic in renal tubules
tubular reabsorption
lipid-solubility
tubular secretion
active diffusion
Drug excretion ↓ Drug excretion ↑
1. Renal excretion tubular secretion tubular reabsorption
Bicarbonate? Penicillin?
pharmacokineticsexcretion
Probenecid?
Plasma(drug)
2. Excretion in bile
liver active transport
Hepato-enteric circulation
intestine
Excretion
portal vein
bile
prolongation of half-life high concentration in bile
Exclusion
pharmacokineticsexcretion
PO
Beneficial for antiinflammatory of cholecystitis
3. Excretion in milk
weak alkaline drugs (morphine,
atropine)
nursing mother
lactiferous Ducts milk (low pH)
reabsorption concentrations in breast milk↑
effects↑
reactions in infant
fat-soluble drugs(sodium pentothal)
dissolved in the milk↑
pharmacokineticsexcretion
If the mather is the addict, whai would be resulted?
pharmacokinetics
Ⅴ.Kinetics and rate process
Differental equation
Kinetics model
KCdt
dC
CPP
PCCC
CKCKdt
dC
CKCKKCdt
dC
1221
2112
Kinetics
K
drug
1 compartmentK12
K 21
Kdrug
2 compartment
pharmacokinetics
1 compartment
Exponentequation
KteCC 0
tt BeAeC
Linear equation
t2.303
-logA)Be-log(C t 303.2
KlogClogC .-
0
t
t303.2
logBlogC
Semi-logarithmicequation
Kinetics
2 compartments
α
T
C
T
C
β
A
B
α
T
logC
T
logC
β
1. Elimination of drugs
pharmacokineticsElimination
0 1 2 3 4 5 …… 9 10 11 12
1st-order 100 50 25 12.5 6.25 3.125
0-order 1000 900 800 700 600 500 …… 100 50 25 12.5
Drugs and their metabolites are eliminated from the body by excretion and metabolism with decrease of drug blood concentration.
Blood concentration of drug is reduced in equal rate or in constant half-life (t1/2). The eliminated rate is direct ratio with blood concentration of a drug.
1KCdt
dC
1) First-order kinetic
t1/2
C
T
one compartment
pharmacokineticsElimination
All most drugs
KCdt
dC
2) Zero-order kinetic
Blood concentration of drug is reduced in equal amount or eliminated in continuant shorten half-life (t1/2).
C
T
0K 0
dCC
dt
0
dCK
dt
3) non-linear kinetics Low dose→ 1st order Overdose→ zero order
T
zero
T
Cfirst
aspirin
Low dose
1st order kinetics T1/2=2-3 h
Large dose Urine pH↓→reabsorption↑
zero order kinetics
T1/2=15-30 hC
salicylic acid, phenytoin, alcohol
The half-life (t1/2) is the time required to decrease the
drug plasma concentration by one-half (50%) during elimination. It is considered that drugs are almost (97%) eliminated after 5 t1/2.
T1/2 is relates to drug character (lipid-solubility, size of
particle, molecular structure, drug interaction) and body condition (function of kidneys and liver…), but generally not relates to drug blood concentration and the routes of administration (therapeutic dose).
4) Half-life of drug (t1/2)
pharmacokineticsElimination
pharmacokineticsElimination
C
TT1/2
C
TT1/2 T1/2
iv
po
t1/2
constant of a drug
Relation todrug character
lipid-solubility, size of particle, molecular structuredrug interaction
Individual variation
No relation to concentration of drug (therapeutic dose)way of administration
Relation tobody condition
KidneysLiver……
When given at a regular interval, a drug plasma conc
entration approximately could reach a plateau after 5 t1/
2.
1) Level of Css relates to:
* dose ↑→Css↑
* interval shorten → wave of Css ↓
intravenous drip → smooth concentration curves.
( the most effective and safe administration)
2. Steady state concentration (Css)
pharmacokineticsSteady state
* When a drug is given at a regular interval, its Css c
ould reached after 5 t1/2;
* loading dose →reaching Css rapidly
When the regular interval is t1/2 and loading dose is d
ouble , Css can be reached immediately in intravenous
injection.
2) Time to reach Css relates to:
pharmacokineticsSteady state
0-order1st-order
C
T
pharmacokineticsSteady state
2D-D D
50%75%
87.5%
93.8%97%
ivd
C
T
T1/2 0 1 2 3 4 5… n
first -order
A. dose 100 100 100 100 100 100
amount 50 75 87.5 93.5 96.9… 100
B. dose 200 200 200 200 200 200
amount 100 150 175 187.5 193.8… 200
C. dose 200 100 100 100 100 100
amount 100 100 100 100 100
zero -order
dose 100 100 100 100 100 100…
amount 50 100 150 200 250…
Steady state concentration
pharmacokineticsSteady state